The TREX1 C-terminal Region Controls Cellular Localization through Ubiquitination

Orebaugh, Clinton D.; Fye, Jason M.; Harvey, Scott; Hollis, Thomas; Wilkinson, John; Perrino, Fred W.

doi:10.1074/jbc.m113.503391

Cited by 34 publications

(32 citation statements)

References 68 publications

(107 reference statements)

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“…The TREX1 Lys-66 is also positioned in the dimer to hydrogen bond across the interface to Glu-198 of the opposing protomer. The TREX1 E198K mutation is found in AGS (14,39), and, in this case, the TREX1 E198K/E198K enzyme exhibits DNA degradation activities indistinguishable from the TREX1 WT enzyme (31). However, we recently showed that the TREX1 E198K enzyme is hyper-ubiquitinated, suggesting a novel mechanism for altered TREX1 DNA degradation dysfunction and disease.…”

Section: Analysis Of Dsdna Binding By Trex1 Wt and Trex1mentioning

confidence: 95%

“…The TREX1 mutant enzymes that cause human disease exhibit a broad range of DNA degradation activities that vary from levels indistinguishable from WT to those diminished by more than five orders of magnitude, with the levels of diminished activities being dependent upon DNA structure (13, 14, 20, 23, 28 -30). The specific TREX1 disease-causing mutations can result in either diminished catalytic function or altered post-translational modification and cellular localization (20,23,31). These varied effects exhibited by TREX1 mutant enzymes on catalytic function and cellular localization might be reconciled with the diversity of human disease pathogenesis to help explain the precise role of TREX1 in DNA degradation to prevent inappropriate immune activation.…”

Section: D200hmentioning

confidence: 99%

“…31 and encodes the most active 3Ј35Ј-exonuclease in multiple mammalian tissues (1)(2)(3)(4)(5)(6)(7). Mutations in the TREX1 gene have now been identified to cause a spectrum of autoimmune disorders, including Aicardi-Goutières syndrome (AGS), 2 Cree encephalitis, familial chilblain lupus (FCL), retinal vasculopathy with cerebral leukodystrophy, and are associated with systemic lupus erythematosus (8 -25).…”

Section: D200hmentioning

confidence: 99%

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The Arg-62 Residues of the TREX1 Exonuclease Act Across the Dimer Interface Contributing to Catalysis in the Opposing Protomers

Fye

Coffin

Orebaugh

et al. 2014

Journal of Biological Chemistry

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Section: Analysis Of Dsdna Binding By Trex1 Wt and Trex1mentioning

confidence: 95%

Section: D200hmentioning

confidence: 99%

Section: D200hmentioning

confidence: 99%

See 1 more Smart Citation

The Arg-62 Residues of the TREX1 Exonuclease Act Across the Dimer Interface Contributing to Catalysis in the Opposing Protomers

Fye

Coffin

Orebaugh

et al. 2014

Journal of Biological Chemistry

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“…So far, the genes implicated include TREX1; SAMHD1; RNASEH2A, B and C; and ADAR1, with recent studies documenting activation of the IFN-I pathway in patients with mutations in ADAR1, responsible for editing of noncoding RNA, and in 90% of AGS patients overall [4, 6]. Variations in these same genes have also been associated with some cases of SLE, although the specific mutations or common variants tend to be distinct from those that account for AGS [7]. …”

Section: Genetic Associationsmentioning

confidence: 99%

Advances in understanding the role of type I interferons in systemic lupus erythematosus

Crow

2014

Current Opinion in Rheumatology

100

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Purpose of Review Advances in understanding the genetic and molecular basis of innate immune system activation and function have supported the hypothesis that type I interferons (IFN-I), essential mediators of anti-viral host defense, are central contributors to the pathogenesis of systemic lupus erythematosus (SLE). This review addresses recent data that support the rationale for therapeutic targeting of the IFN-I pathway in SLE. Recent Findings New insights into mechanisms of cell-intrinsic innate immune system activation, driven by endogenous virus-like nucleic acids and potentially modified by environmental stressors, provide a model for induction of IFN-I that may precede clinically apparent autoimmunity in patients with lupus. Further amplification of IFN-α production, induced by nucleic acid-containing immune complexes that activate endosomal Toll-like receptors, augments and sustains immune system activation, autoimmunity and tissue damage. Summary As demonstrated in murine studies of persistent virus infection accompanied by sustained production of IFN-I, blockade of the IFN-I pathway may reverse the immune dysregulation and tissue damage that are essential features of the immunopathogenesis of SLE. Recent research progress has identified numerous therapeutic targets, and specific candidate therapeutics relevant to the IFN-I pathway are under investigation.

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“…Different TREX1 mutations have been reported in AicardiGoutière syndrome [11], systemic lupus erythematosus [12] and familial chilblain lupus [13]. These latter mutations involve the enzymatic sites of the protein, leading to exonuclease dysfunction and possibly causing the accumulation of aberrant DNA [14] or post-translational modification through ubiquitination [15].…”

Section: Introductionmentioning

confidence: 99%

TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy

et al. 2014

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Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.

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The TREX1 C-terminal Region Controls Cellular Localization through Ubiquitination

Cited by 34 publications

References 68 publications

The Arg-62 Residues of the TREX1 Exonuclease Act Across the Dimer Interface Contributing to Catalysis in the Opposing Protomers

The Arg-62 Residues of the TREX1 Exonuclease Act Across the Dimer Interface Contributing to Catalysis in the Opposing Protomers

Advances in understanding the role of type I interferons in systemic lupus erythematosus

TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy

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